What is Neuromyelitis Optica Spectrum Disorder (NMOSD)?

What is Neuromyelitis Optica Spectrum Disorder (NMOSD)?

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neuroinflammatory disease of the central nervous system that primarily attacks the optic nerves, spinal cord, and brainstem, characterized by the presence of aquaporin-4 antibodies (AQP4-IgG) in approximately 75% of cases, and distinguished from multiple sclerosis by its relapsing course without progressive disability between attacks. 1, 2

Core Pathophysiology

• NMOSD is an antibody-mediated astrocytopathy where serum immunoglobulin G autoantibodies target aquaporin-4 (AQP4-IgG), the most prevalent water-channel protein in the central nervous system 1
• The disease causes severe immune-mediated demyelination and axonal damage predominantly affecting optic nerves and spinal cord 3
• Approximately 75% of patients test positive for AQP4 antibodies, while the remaining 25% are seronegative (some may have anti-MOG antibodies) 2, 4

Classic Clinical Presentations

The three hallmark clinical syndromes that should immediately raise suspicion for NMOSD include:

• Severe optic neuritis: Often bilateral and simultaneous, with posterior optic nerve involvement extending to the chiasm, and long optic nerve lesions on MRI 4, 5
• Longitudinally extensive transverse myelitis (LETM): Spinal cord inflammation spanning ≥3 contiguous vertebral segments 6, 4
• Area postrema syndrome: Intractable vomiting and hiccoughs due to brainstem lesions affecting the area postrema 2, 4

Critical Distinguishing Features from Multiple Sclerosis

NMOSD differs fundamentally from MS in several key ways:

• Lesion distribution: NMOSD lesions preferentially affect deep white matter over periventricular regions, with "cloud-like" poorly marginated corpus callosum lesions and diencephalic involvement 4
• Spinal cord involvement: LETM (≥3 vertebral segments) is characteristic of NMOSD, whereas MS typically shows short, discrete spinal lesions 6, 4
• Optic nerve pattern: NMOSD presents with bilateral simultaneous involvement, posterior extension to chiasm, and long optic nerve lesions, while MS typically shows unilateral, short anterior lesions 4, 5
• Disease course: NMOSD follows a relapsing pattern without progressive disability between attacks, whereas MS often shows progressive accumulation of disability 2

Diagnostic Criteria

The International Panel on Multiple Sclerosis recommends that definite NMOSD requires:

• Optic neuritis AND acute myelitis AND at least 2 of the following 3 supportive criteria 4:
  • Contiguous spinal cord MRI lesion extending ≥3 vertebral segments
  • Brain MRI at onset nondiagnostic for MS
  • NMO-IgG (aquaporin-4 antibody) seropositivity

For AQP4-IgG positive patients, revised criteria allow diagnosis with at least one core clinical characteristic (optic neuritis, myelitis, area postrema syndrome, brainstem syndrome, diencephalic syndrome, or cerebral syndrome) 6

For AQP4-IgG negative or unknown status patients, more stringent clinical criteria with additional neuroimaging findings are required 6

Prognosis Without Treatment

The natural history of untreated NMOSD is devastating:

• Approximately 50% of untreated patients become wheelchair users and blind 2
• One-third of patients die within 5 years of their first attack 2
• Disability accrual is directly related to relapses, not progressive disease between attacks 2
• A progressive clinical course is very unusual in NMOSD 2

Imaging Characteristics

MRI features that distinguish NMOSD include:

• Spinal cord: Longitudinally extensive lesions (≥3 segments), often with central cord involvement and associated swelling 6
• Optic nerves: T2 hyperintensity with gadolinium enhancement extending over half the optic nerve length or involving the optic chiasm 6, 5
• Brain: "Cloud-like" poorly marginated lesions, area postrema involvement, diencephalic lesions, and periependymal brainstem lesions 4, 6
• Contrast enhancement: Active demyelinating lesions show enhancement in the first 4-6 weeks, representing inflammatory infiltrates causing blood-brain barrier breakdown 6

Critical Pitfalls to Avoid

• Do not delay diagnosis waiting for dissemination in space: Many MOG-EM and NMOSD patients present with isolated syndromes (isolated LETM, isolated bilateral optic neuritis, or isolated brainstem encephalitis) that warrant immediate testing 6
• Do not assume all NMOSD is AQP4-positive: Approximately 25% are seronegative, and some may have anti-MOG antibodies requiring different management considerations 4, 2
• Do not confuse transient criteria fulfillment with definite diagnosis: Up to 7.2% of clinically isolated syndromes may transiently meet some NMO criteria, but only 0.3% meet full diagnostic criteria 4
• Do not treat as MS: NMOSD requires different therapeutic approaches, and some MS treatments (particularly interferon-beta) may worsen NMOSD 6

Epidemiology

• NMOSD has a global prevalence of 1-5 per 100,000 population 7
• The disease is rare but increasingly recognized due to improved diagnostic criteria and antibody testing 1, 8